PROJECT SUMMARY The recent global emergence of Henipaviruses (HNVs) into human populations changes the risk calculus associated with the species. We see a specific need for a vaccine strategy and passive immunotherapies that will protect not only against HNVs that have previously emerged, but also diverse HNVs should zoonotic spillover and viral emergence occur from one the many divergent HNVs. The objectives of this proposal are to leverage our expertise on the functional and antigenic diversity of the HNV surface glycoproteins in designing a rational vaccine strategy against HNVs and to better understand the antibody response to the HNV glycoproteins. We do so by 1) performing a vaccination strategy that will exploit the conserved mode of host receptor ephrinB2 interaction amongst the diverse spectrum of HNV receptor attachment glycoproteins in order to generate broadly neutralizing antibodies and by 2) characterizing the conserved, vulnerable epitopes these antibodies target in the surface glycoproteins. We will use an array of virological, immunological, structural, and biochemical methods to address these aims. Combined, these approaches will generate novel broadly neutralizing antibodies against the ever-expanding spectrum of HNVs and reveal conserved regions of the HNV glycoproteins that can be exploited in future vaccination strategies.